1. Field of the Invention
This invention relates to a new class of selective and potent inhibitors of platelet cyclic AMP phosphodiesterase. In particular, the invention relates to a series of new carboxamido derivatives of imidazo[4,5-b]quinolin-2-one which are useful as inhibitors of ADP-induced aggregation of human blood plateletes in platelet-rich-plasma.
2. Description of the Art
Platelet aggregation is considered part of a complex physiological mechanism for formation of a thrombus in the vascular system. Thromboembolic phenomena, i.e., the formation of thrombi, are involved in hemostasis and a number of diseased states in mammals including thrombophlebitis, phlebothrombosis, cerebral thrombosis, coronary thrombosis and retinal vessel thrombosis. An increase in propensity for platelet aggregation, sometimes referred to as platelet adhesiveness, is observed following parturition, surgical operations such as coronary artery bypass surgery, organ transplant, angioplasty, prosthetic heart valve implants to name a few; and in ischemic heart disease, atherosclerosis, multiple sclerosis, intracranial tumors, thromboembolism, and hyperlipemia (A. Poplawski, et al, J. Atherosclerosis Research. 8: 721 (1968)).
The imidazo[4,5-b]quinolin-2-one derivatives have been identified as potent inhibitors of human blood platelet cAMP phosphodiesterase (PDE) and in vitro aggregation induced by ADP and collagen (Seiler et al., Thromb. Res., 62, 31-42 (1991).
The heterocycle "2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinoline" of the formula (1), alternately referred to as 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one, was described by Kozak, et al, Bull. Intern. Acad. Polanaise, 1930A, 432-438 (Chem. Abs. 25, 5400) ##STR3##
Derivatives of formula (1) having cyclic AMP phosphodiesterase inhibitory activity have been prepared and studied for their platelet inhibition and cardiotonic properties. Thus, for example:
Meanwell, N. A., U.S. Pat. No. 4,943,573 describes a series of 2,3-dihydro-2-oxo-1H-imidazo-[4,5-b]quinolin-2-ones comprising derivative of the formula (2) ##STR4## wherein n is 3 to 5; R.sup.1 is hydrogen or alkyl of 1 to 4 carbon atoms; R.sup.2 is hydrogen; R.sup.3 is 1-piperidinylethyl, 1-benzylpiperidin-4-yl, 4-(1-piperidinyl)piperidine, (1-alkyl-2-pyrrolidinyl)alkyl where alkyl is 1 to 4 carbon atoms, 3-quinuclidinyl; R.sup.2 and R.sup.3 together with the nitrogen atom to which they are attached form 4-R.sup.4 -piperazin-1-yl wherein R.sup.4 is alkyl of i to 7 carbon atoms, alkoxyethyl of 3 to 7 carbon atoms, pyridinyl, pyrimidinyl, tetrahydropyranylmethyl, thienylmethyl, cycloalkyl-(CH.sub.2).sub.m where m is zero or one and cycloalkyl is 5 to 7 carbon atoms except m is zero when cycloalkyl is 7 carbon atoms, benzyl, 4-fluorobenzyl, 3-trifluoromethylbenzyl, 4-alkoxybenzyl where alkoxy is 1 to 4 carbon atoms.
Among the compounds disclosed is the compound of the formula (3), identified as 1-(cyclohexylmethyl)-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-ylox y)1-oxybutyl]piperazine. ##STR5##
Meanwell, et al. U.S. Pat. No. 4,775,674 describe a series of 2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolinyl ether derivatives of the formula (4) ##STR6## wherein R.sup.1 is hydrogen, lower alkyl, benzyl; R.sup.2 is hydrogen, halogen, lower alkyl, lower alkoxy; Alk is alkylene; Y is hydroxy and alkanoic or aralkanoic esters thereof, oxo ketone, dialkylamino carboxylic acid and esters, carboxamides, alkoxy, ethanolamines and cyclic carbamates thereof, tetrazoyl, and optionally substituted phenylsulfonyl.
Among the compounds disclosed is the compound of formula (5), identified in the art as 7-[4 -(phenylsulfonyl)butoxyl]-1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-one. ##STR7##
Meanwell, et al, U.S. Pat. No. 4,701,459 describe another series of 2,3-dihydro-2-oxo-1H-imidazo-[4,5-b]quinoline compounds comprising amine derivatives of formula (6) ##STR8## wherein R.sup.1 is hydrogen, lower alkyl; R.sup.2 is hydrogen, lower alkyl, lower alkoxy, halogen; R.sup.3 is hydrogen, lower alkyl; R.sup.4 is hydrogen, lower alkyl, alkanoyl, phenylalkanoyl wherein phenyl is optionally substituted with halogen, lower alkyl, lower alkoxy, R.sup.3 and R.sup.4 are joined together to form morpholinyl, piperidinyl or pyrrolidinyl optionally substituted with --CO.sub.2 R.sup.5 or ##STR9## wherein R.sup.5 is hydrogen or lower alkyl, and R.sup.6 is hydrogen, lower alkyl, cycloalkyl; 4-R.sup.7 -piperazinyl wherein R.sup.7 is --CO.sub.2 R.sup.8 wherein R.sup.8 is lower alkyl, phenyl optionally substituted with up to 2 halogen, lower alkyl or lower alkoxy: phenylalkanoyl of 7 to 10 carbon wherein phenyl is unsubstituted or independently substituted with up to 2 halogen, lower alkyl, lower alkoxy.
Meanwell, et al. U.S. Pat. No. 4,668,686 describe still another series of 1,3-dihydro-2H-imidazo-[4,5-b]quninolin-2-ones comprising derivatives of formula (7) ##STR10## wherein R.sup.1 is halogen, lower alkyl, lower alkoxy, trifluoromethyl; R.sup.2 is hydrogen, halogen, lower alkyl, lower alkoxy; R.sup.3 is hydrogen, halogen, lower alkyl, lower alkoxy; and R.sup.4 is hydrogen or lower alkyl.
Another class of heterocyclic compounds having phosphodiesterase inhibiting and anti-platelet aggregation activity comprise the tetrahydroimidazo[2,1-b]quinazolin-2-ones of formula (8) ##STR11##
For example:
Beverung, Jr., et al, U.S. Pat. No. 3,932,407 disclose a series of compounds useful as blood platelet antiaggregative and/or antihypertensive and/or bronchodilator agents of tetrahydroimidazo[2,1-b]-quinazolin-2-one class. Anagrelide (9), a particularly preferred member of the Beverung, Jr., et al. series, has been studied extensively, e.g., J. S. Fleming, et al, New Drugs Annual: Cardiovascular Drugs, Raven Press, 277-294, NY (1983). ##STR12##
Chodnekar, et al. U.S. Pat. No. 4,256,748 describe a series of tetrahydroimidazo[2,1-b]quinazolin-2-ones of the formula (10) as inhibitors of the aggregation of blood platelets and cardiotonic activity. ##STR13##
Representative of the Chodneker compounds are RO 15--2041 (R.sup.4 .dbd.CH.sub.3, R.sup.3 .dbd.H, R.sup.2 .dbd.6--CH.sub.3, R.sup.1 .dbd.7--Br) and RO 13--6438 (R.sup.4 .dbd.CH.sub.3, R.sup.3 .dbd.H, R.sup.2 .dbd.6--CH.sub.3, R.sup.1 .dbd.H).
Jones, et al, U.S. Pat. No. 4,490,371 describe another series of tetrahydroimidazo[2,1-b]quinazolin-2-one derivatives as cyclic AMP phosphodiesterase inhibitors useful as thrombogenic agents. Among the compounds disclosed is the formula (11) amide, identified in the art as lixazinone. ##STR14##
Jones, et al, European Patent Application 153152 further describe tetrahydroimidazo[2,1-b]quinazolin-e-ones of formula (11) as cyclic AMP phosphodiesterase inhibitors useful as antithrombogenic agents. ##STR15##
Compounds of the aforementioned patents generally display limited solubility in water, acidic or alkali media and common organic solvents.